Two-Step Mechanism of Membrane Disruption by Aβ through Membrane Fragmentation and Pore Formation.

Department of Chemistry, University of Michigan, Ann Arbor, Michigan.
Biophysical Journal (Impact Factor: 3.83). 08/2012; 103(4):702-10. DOI: 10.1016/j.bpj.2012.06.045
Source: PubMed

ABSTRACT Disruption of cell membranes by Aβ is believed to be one of the key components of Aβ toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by Aβ occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addition of freshly dissolved Aβ(1-40), defects form on the membrane that share many of the properties of Aβ channels originally reported from single-channel electrical recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we observed that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved Aβ(1-40) is weakly observed in the absence of gangliosides, fiber-dependent membrane fragmentation can only be observed in their presence. These results provide insights into the toxicity of Aβ and may aid in the design of specific compounds to alleviate the neurodegeneration of Alzheimer's disease.

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Available from: Jeffrey R Brender, Jul 10, 2015
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    • "Taken together, these data strongly suggested that the AMP properties of Ab 1-42 differed significantly from those of LL-37 and further suggested that Ab 1-42 initiated its anti-viral effects prior to HSV-1 entry into the cells. Studies using model membranes (Jang et al. 2013; Masters and Selkoe 2012; Zhao et al. 2012; Sciacca et al. 2012), human neurons and mouse fibroblasts (Jang et al. 2010) have shown that Ab peptides can insert into lipid bilayers and form toxic ion channels that destabilize cellular ionic balance. Therefore, we tested the possibility that this mechanism could explain the anti-viral activity of Ab peptides. "
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    ABSTRACT: Amyloid plaques, the hallmark of Alzheimer's disease (AD), contain fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1) has been implicated as a risk factor for AD and found to co-localize within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial, anti-yeast and anti-viral activities. Here, fibroblast, epithelial and neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1 replication when added 2 h prior to or concomitantly with virus challenge, but not when added 2 or 6 h after virus addition. In contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the non-enveloped human adenovirus. In comparison, antimicrobial peptide LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1 in a cell-free system and prevented viral entry into cells. The sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1 envelope. Our data suggest that Aβ peptides represent a novel class of antimicrobial peptides that protect against neurotropic enveloped virus infections such as HSV-1. Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.
    Biogerontology 11/2014; 16(1). DOI:10.1007/s10522-014-9538-8
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    • "This finding led us to propose that the increase in Ca 2+ permeability observed in cells exposed to Aβ results from the activity of calcium ion channels formed by Aβ in the cell surface membrane (Arispe et al. 1994a, b) (Arispe et al. 2010). While there is a growing consensus that Aβ peptides increase membrane conductance by forming conductive pores (Aguayo et al. 2009; Parodi et al. 2010; Sepulveda et al. 2010; Schauerte et al. 2010; Johnson et al. 2011; Tofoleanu and Buchete 2012; DeMuro et al. 2011; Sciacca et al. 2012; Prangkio et al. 2012; Schauerte et al. 2010; DeMuro et al. 2011), there has not been a systematic study on how a "
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    ABSTRACT: Interaction of the Alzheimer's Aβ peptides with the plasma membrane of cells in culture results in chronic increases in cytosolic [Ca(2+)]. Such increases can cause a variety of secondary effects leading to impaired cell growth or cell degeneration. In this investigation, we made a comprehensive study of the changes in cytosolic [Ca(2+)] in single PC12 cells and human neurons stressed by continuous exposure to a medium containing Aβ42 for several days. The differential timing and magnitude of the Aβ42-induced increase in [Ca(2+)] reveal subpopulations of cells with differential sensitivity to Aβ42. These results suggest that the effect produced by Aβ on the level of cytosolic [Ca(2+)] depends on the type of cell being monitored. Moreover, the results obtained of using potent inhibitors of Aβ cation channels such as Zn(2+) and the small peptide NA7 add further proof to the suggestion that the long-term increases in cytosolic [Ca(2+)] in cells stressed by continuous exposure to Aβ is the result of Aβ ion channel activity.
    Cell Stress and Chaperones 11/2014; 20(2). DOI:10.1007/s12192-014-0551-2
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    • "Indeed, oligomeric complexes of Aβ or α-syn may penetrate cell membranes, stimulating Ca 2+ influx and leading to cell death [16] [17] [18]. The mechanism of lipid bilayer disruption by aggregate species may involve insertion of distinct pore-like structures, formation of large " defects " in the membrane , or a combination of both [19] [20] [21] [22] [23] [24]. Moreover, the first study has been recently published demonstrating increased phospholipid vesicle leakage, in association with decreased cell viability, induced by tau aggregation intermediates [25]. "
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    ABSTRACT: Alzheimer's disease and Parkinson's disease are neurodegenerative disorders characterized by the misfolding of proteins into soluble prefibrillar aggregates. These aggregate complexes disrupt mitochondrial function, initiating a pathophysiological cascade leading to synaptic and neuronal degeneration. In order to explore the interaction of amyloid aggregates with mitochondrial membranes, we made use of two in vitro model systems, namely: (i) lipid vesicles with defined membrane compositions that mimic those of mitochondrial membranes, (ii) respiring mitochondria isolated from neuronal SH-SY5Y cells. External application of soluble prefibrillar forms, but not monomers, of amyloid-beta (Aβ42 peptide), wild-type α-synuclein (α-syn), mutant α-syn (A30P and A53T) and tau-441 proteins induced a robust permeabilisation of mitochondrial-like vesicles, and triggered Cytochrome c release (CCR) from isolated mitochondrial organelles. Importantly, the effect on mitochondria was shown to be dependent upon cardiolipin, an anionic phospholipid unique to mitochondria and a well-known key player in mitochondrial apoptosis. Pharmacological modulators of mitochondrial ion channels failed to inhibit CCR. Thus, we propose a generic mechanism of thrilling mitochondria in which soluble amyloid aggregates have the intrinsic capacity to permeabilise mitochondrial membranes, without the need of any other protein. Finally, six small-molecule compounds and black tea extract were tested for their ability to inhibit permeation of mitochondrial membranes by Aβ42, α-syn and tau aggregate complexes. We found that black tea extract and rosmarinic acid were the most potent mito-protectants, and may thus represent important drug leads to alleviate mitochondrial dysfunction in neurodegenerative diseases.
    Biochimica et Biophysica Acta 06/2013; 1828(11). DOI:10.1016/j.bbamem.2013.06.026
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Questions & Answers about this publication

  • Jeffrey R Brender added an answer in Amyloid Beta-Peptides:
    Amyloid beta peptide (22-35), (16-22). How are these fragments biologically relevant?
    In literature interaction of Amyloid beta peptide with membrane sometimes attributed to the fragments (22-35) or (16-22). As they are the transmembrane components of the peptide. Assuming that, I am wondering about biological relevance of these fragments compare to the whole peptide (1-40, 1-42)?
    Jeffrey R Brender · University of Michigan
    If you are working with membrane disruption by Abeta you may want to look at this paper:
    For general information on amyloids you want to look at this thread and join the project associated with it: